Introduction <p>Primary liver cancer is associated with high morbidity and mortality rate. In about 50% of cases, primary liver cancer is related to the phosphoinositide-3-kinase (PI3K)/Akt signaling pathway. Wogonoside is an active component extracted from Scutellaria baicalensis. Its antitumor effects in liver cancer are scarcely known.</p> Aim <p>This study explores the correlation between wogonoside and the PI3K/Akt signaling pathway in liver cancer in vitro.</p> Methods <p>THLE-2 cells and HepG2 cells were treated with different concentrations of wogonoside to establish low-, medium- and high- dose groups, and the concentration of each dose group was determined by CCK-8 assay. Subsequent experiments were evaluated the viability, proliferation, invasion, wound healing, apoptosis rate of HepG2 cells, as well as the expression levels of relevant targets. In silico network pharmacology was performed to investigate the relationship between wogonoside and the PI3K/Akt signaling pathway, providing insights into the connection between wogonoside and liver cancer.</p> Results <p>Compared with the control group, the viability, proliferation, invasion, migration and wound healing ability of wogonoside-treated HepG2 cells were significantly declined in a dose- and time-dependent manner. Wogonoside significantly reduced the relative expression level of Bcl-2/Bax relative protein. Wogonoside also decreased the relative protein expression of phospho-PI3K/PI3K and phospho-AKT/AKT and the mRNA levels of PI3K and AKT. In addition, potential key genes, biological processes, and pathways associated with the therapeutic effects of wogonoside on liver cancer were explored.</p> Conclusion <p>Wogonoside can alleviate the proliferation and promote the apoptosis of HepG2 cells, which may be related to the PI3K/Akt signaling pathway.</p>